p2013_20 Harringtonolide

Stereoselective Total Synthesis of
Hainanolidol and Harringtonolide
via Oxidopyrylium-based (5+2)
Cycloaddition
M. Zhang, N. Liu, W. Tang
University of Wisconsin
J. Am. Chem. Soc. 2013, 135, 12434-12438
2
Introduction
•  Cephalotaxus norditerpenes (C19)
•  Tetracyclic carbon framework
•  Ring A: 5-6 contiguous stereogenic centers
•  Tropone ring D
•  1 and 4 with additional THF ring
3
Introduction
•  Harringtonolide first isolated in 1978
•  from C. harringtonia
•  Structure confirmed by X-ray.
•  In 1979, harringtonolide and hainanolidol isolated from
C. haiananensis.
Antiviral activity
Antineoplasmic activity (nM range)
Inactive
Same plant
Different biosynthesis
THF ring seems to be important for activity: interest in determining mode of action!
4
Biosynthesis
•  No study has been conducted!
•  Proposition
H. Abdelkafi and B. Nay, Nat. Prod. Rep. 2012, 29, 845-869
5
First Semi-synthesis
hainanolidol is the biosynthetic precursor of harringtonolide
Z. Xue, N. J. Sun, and X. T. Liang, Acta Pharm. Sinica, 1982, 17, 236-237
6
Nay Strategy to the Asymmetric Harringtonolide Core
Strategy based on IMDA approach
SM = glucose!
H. Abdelkafi et al., Eur. J. Org. Chem. 2011, 2789-2800
7
Nay Strategy to the Asymmetric Harringtonolide Core
Retrosynthesis of D-ring
H. Abdelkafi et al., Eur. J. Org. Chem. 2011, 2789-2800
8
Nay Strategy to the Asymmetric Harringtonolide Core
H. Abdelkafi et al., Eur. J. Org. Chem. 2011, 2789-2800
9
Nay Strategy to the Asymmetric Harringtonolide Core
H. Abdelkafi, P. Herson, and B. Nay, Org. Lett. 2012, 14, 1270-1273
10
Nay Strategy to the Asymmetric Harringtonolide Core
H. Abdelkafi, P. Herson, and B. Nay, Org. Lett. 2012, 14, 1270-1273
11
Nay Strategy to the Asymmetric Harringtonolide Core
Conditions: Yb(OTf)3 (1eq.), THF, 80 °C, yield: 57%
H. Abdelkafi, P. Herson, and B. Nay, Org. Lett. 2012, 14, 1270-1273
12
Zhang Retrosynthesis
13
5+2 cycloaddition
5+2 addition via group elimination
Oxidation of furan: Achmatowicz reaction
14
5+2 cycloaddition
G. Pattenden et al., Org. biomol. Chem., 2009, 7, 639
15
5+2 cycloaddition
Biosynthetically inspired total synthesis of intricarene for bipinnatin J
P. A. Roethle, P. T. Hernandez, D. Trauner, J. Org. Chem., 2006, 8, 5901-5904
16
Synthesis
Preparation of starting material
O
EtO2C
O
+
O
O
Cu(OTf)2
THF, 50 °C, 3d
EtO2C
Pyrrolidine, acetic acid
EtOAc, 50 °C, 24h
EtO2C
O
65% (17.8 g, 65%)
Addition of different chiral ligand failed
to give good yield and ee!
J. A. Marshall, H. Faubl, T. M. Warne, Chem. Commun. 1967, 753
17
Synthesis
O
9
EtO2C
1) TMSCl, NaI, Ac2O
0°C to rt
85%
EtO2C
EtO2C
LDA, TESCl
then, OsO4, NMO
O
2) Oxone, NaHCO3
70%
OH 10
OH
O
THF/H2O (10:1)
72%
OTES
11
NaBH(OAc)3 Acetone, TsOH
AcOH, MeCN
74%
72%
dr >20:1
EtO2C
EtO2C
O
O
O
13
O
Dess-Martin period.
O
76%
OTES 12
Cis-diol obtained because protection as acetonide possible
Need the trans-diol!
18
Synthesis: trans-diol
EtO2C
OH
O
OTES
11
NaBH4,
then TBSOTf,
2.6-lutidine
84% over 2 steps
dr >20:1
EtO2C
OTBS
OTBS
OH
14B
EtO2C
NaBH4
93%
dr >20:1
EtO2C
OTBS
OTBS
Dess-Martin period.
84%
15
OTBS
OTBS
OH
O
TFA
76%
14
19
Synthesis: Weinreb amide 18
EtO2C
OTBS
OTBS
OH
14B
Hg(TFA)2
vinylbutylether
Et3N
86%
EtO2C
EtO2C
OTBS
OTBS
O
16
toluene, reflux,
85%
dr >20:1
OHC
OTBS
Pinnick ox.
then MeOHNMe x HCl
PyBOP, Et3N
OTBS
76% over two steps
EtO2C
OTBS
OTBS
O
17
N
18
OMe
20
Synthesis
EtO2C
EtO2C
OTBS
OTBS
Mn(OAc)3, TBHP
76%
O
N
O
OTBS
O
18
OMe
OTBS
N
TsNHNH2,
Then catechol borane
and NaOAc
75% over 2 steps
dr >20:1
19
Via:
OTBS
OTBS
O
N
OMe
G. V. Kabalka, D. T. C. Yang and J. D. Baker, J. Org. Chem. 1976, 41, 574-576
EtO2C
21
OMe
21
Synthesis
EtO2C
OTBS
OTBS
O
N
21
OMe
EtO2C
Furan, BuLi,
MgBr2
OTBS
92%
OTBS
O
22
O
NaBH4,
Then VO(acac)2,
TBHP, DCM
87% over 2 steps
Ac2O, DMAP
pyridine,
91%
EtO2C
OTBS
OTBS
AcO
O
23
O
22
Completion of the synthesis
EtO2C
OTBS
OTBS
AcO
O
23
O
Opening of the ether bridge proved impossible!
23
Alternative strategy
2 Step sequence: SN1’ Substitution with thiophenol and deprotonation
Model:
(tropone installation)
24
Model: Tropone formation
Hetero Diels-Alder reaction with nitrosoarene
This strategy proved not successful on the elaborated intermediate!
Hydrolysis of thio ether not possible as well!
25
Removal of thio ether
1)  Protection of alcohol
2)  Oxidation of thiol to sulfoxide
3)  Reduction using SmI2
Reduction with SmI2 known for sulfone!
26
Completion of the synthesis
TsOH
Pb(OAc)4
CDCl3
85%
benzene, 90°C
52%
27
Conclusion
Synthesis of haianolidol featuring:
1)  2 stereoselective 3+3 sigmatropic rearrangement
2)  Oxydopyrylium-based 5+2 cycloaddition
3)  Formation of tropone
This synthesis will allow preparation of derivatives and investigation of the mode
of action.
28
Biosynthesis
29
Synthesis of chiral template
M. Fengler-Veith, O. Schwardt, U. Kaut, B. Krämer, and V. Jäger, Org. Synth., 2004, 78, 123
30
Synthesis of chiral template
31
IMDA Selectivity
32
Diastereoselectivity
33
Diol into double bond
P. J. Garegg, B. Samuelsson, Synthesis, 1979, 469
34
Oxidation Mn (III)
35
Oxidation VO(acac)2
36
Mercury salt assisted vinylation
VINYLETHSRSBY VINY~TRANSETHERIFICATION
June 5 , 1057
HgOAc + f AcO-
Hg( 0Ac)z
HgOAc’
+ R O C H x C H z + R’OH Jr
RO
\
/
CHCHzHgOAc
\
CHCHzHgOAc
/
(4b)
I
R ’0
RO
+ H+
(4a)
+ ROCH=CHz + R’OH
R‘O
1
rRO
I>
CHCHz-
I1
RO
\
/
CHCHzHgOAc
Hg
+ HOAC
(4~)
ti
+ R’OCH=CHz + ROH
RO
ogous intermediate for vinyl transesterification
(111) should also possess the property of reverting
either to starting reactants or products, thus
explaining the equilibrium character of this reaction.
The 2-acetoxymercuri-1,l-diet
found to be decomposed readily b
ethyl vinyl ether and ethyl alcoh
lishing that such a structure is i
weak acid. This demonstration
although not a sufficient condition
be an intermediate in vinyl tran
We are led to the proposal of step
reacts further with vinyl ether to g
11, by our observation that the 2acetals in the absence of added ace
as phenyl mercuric acetate, both
pounds with a single acid anion) ar
catalysts for vinyl transetherificatio
that structures RHgCH2CH(OR)
phenyl or (R0)2CHCH2-, may be fo
acetic acid, and may subsequently
by this acid. As expected, diwhich is relatively stable to cleava
bond, has no catalytic activity.
Acknowledgment.-We wish to t
Loeffler for much helpful advice and
during the course of this work.
Experimental
Materials.-All vinyl ethers used as vin
cept ethyl vinyl ether and 2-ethylhexyl
were commercially available, were prepa
lyzed high-pressure vinylation of the alc